Spinal muscular atrophy

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Spinal muscular atrophy ( SMA ) is a rare neuromuscular disorder characterized by loss of motor neurons and progressive muscle wasting, often leading to premature death.

This disorder is caused by a genetic defect in the SMN1 gene, which encodes SMN, a protein widely expressed in all eukaryotic cells (ie cells with nuclei, including human cells) and necessary for motor survival. neurons. Lower protein levels lead to loss of function of nerve cells in the anterior horn of the spinal cord and subsequent systemic skeletal atrophy.

Spinal muscular atrophy manifests in varying degrees of severity, all of which have similarities in progressive muscle wasting and impaired mobility. Proximal muscles, arm and leg muscles closer to the torso and respiratory muscles are affected first. Other body systems can also be affected, especially in the form of initial disturbances. SMA is the most common genetic cause of infant death.

Spinal muscular atrophy is a congenital disorder and is autosomally recessive (see explanation of autosomal recessive inheritance video). In December 2016, nusinersen became the first approved drug to treat high school while several other compounds remained in clinical trials.

Video Spinal muscular atrophy

Classification

SMA manifests at various levels of severity, affecting infants through adults. The spectrum of the disease is divided into 3-5 types, corresponding to the age of symptom onset or with the achievement of achievement of the highest motor development.

The most commonly used classifications are as follows:

The most severe form of type I SMA is sometimes called SMA type 0 (or, boyish high school) and diagnosed in very born infants is so weak that they can survive for only a few weeks even with intensive breathing. support. SMA type 0 should not be confused with SMARD1 which may have very similar symptoms and of course but have different genetic causes of high school.

Motor development in people with high school is usually assessed using a validated functional scale - CHOP INTEND (Children's Hospital of Philadelphia Neuromuscular Neurological Tests) at SMA1; and Motor Function Measurement scale or one of several variants of Hammersmith Functional Motor Scale in SMA types 2 and 3.

The eponymous label Werdnig-Hoffmann's disease (sometimes misspelled with one n ) refers to the early clinical description of high school childhood by Johann Hoffmann and Guido Werdnig. The eponymous term of Kugelberg-Welander's disease was after Erik Klas Hendrik Kugelberg (1913-1983) and Lisa Welander (1909-2001), who distinguished the SMA from muscular dystrophy. Rarely used Dubowitz's disease (not to be confused with Dubowitz's syndrome) is named after Victor Dubowitz, an English neurologist who wrote several studies on the high school phenotype.

Maps Spinal muscular atrophy

Signs and symptoms

Symptoms vary depending on the type of SMA, stage of the disease as well as individual factors. The following signs and symptoms most often occur in severe Type 0/I SMAs:

• Areflexia, especially on extremities
• Overall muscle weakness, poor muscle tone, limpness or a tendency to fail
• Difficulty achieving progress, difficulty sitting/standing/walking
• In young children: adopt the position of frog legs when sitting (hips kidnapped and knees bent)
• Loss of strength of respiratory muscles: weak cough, weak cry (baby), accumulation of secretions in the lungs or throat, respiratory disturbance
• Bleach-shaped body (caused by only using the abdominal muscles to breathe) on a heavy school type
• Fasciculations (twitches) of the tongue
• Difficulty sucking or swallowing, feeding poor

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Cause

Spinal muscular atrophy is associated with genetic mutations in the SMN1 genes.

The human 5 chromosome contains two virtually identical genes at location 5q13: telomeric copy of SMN1 and centromeric copy SMN2 . In healthy individuals, the SMN1 gene encodes the viability of motor neurone proteins (SMN) which, as the name implies, plays an important role in the survival of motor neurons. The SMN2 gene, on the other hand - due to variations in a single nucleotide (840.C-> T) - undergoes alternative splicing at inton intron 6 to exon 8, with only 10- 20% of SMN2 functional survival coding transcript of motor neuron protein (SMN-fl) and 80-90% of the transcript yields a truncated protein compound (SMN? 7) that is rapidly degraded in the cell.

In individuals affected by SMA, the SMN1 gene mutates in such a way that it can not encode the SMN protein properly - due to the deletion occurring in exon 7 or other point mutations (often resulting in functional conversions of SMN1 sequence being SMN2 ). Almost everyone, however, has at least one functional copy of the SMN2 gene (with most having 2-4 of them) that still encodes a small amount of SMN protein - about 10-20% of the normal level - allowing some neurons to survive. However, in the long run, reduced availability of the SMN protein produces gradual motor neuron cell death in the anterior horn of the spinal cord and brain. Muscles that depend on these motor neurons for nerve inputs now decrease innervation (also called denervation), and therefore decrease in input from the central nervous system (CNS). Decreased transmission of impulses through motor neurons leads to a decrease in denuclear muscle contractile activity. As a result, denervated muscles have progressive atrophy (throw away).

Lower limb muscles are usually affected first, followed by upper limb muscles, spine and neck and, in more severe cases, lung muscles and mastication. Proximal muscles are always affected early and larger than distal.

The severity of high school symptoms is broadly related to how well the remaining SMN2 genes can replace the loss of the SMN1 function. This is partly related to the number of copies of the SMN2 gene present on the chromosome. While healthy people carry two copies of the SMN2 gene, people with high school can have anything between 1 and 4 (or more) of them, with the larger number of SMN2 copies, more mild disease severity. Thus, most high school type I babies have one or two copies of SMN2 ; people with SMA II and III typically have at least three copies of SMN2 ; and people with SMA IV usually have at least four of them. However, the correlation between symptom severity and number of copies of SMN2 is not absolute, and there appears to be other factors affecting the phenotype of the disease.

Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means that the defective gene lies in the autosomes. Two copies of the defective gene - one from each parent - are required to inherit the disorder: the parents may be carriers and not personally affected. SMA appears to appear de novo (ie, without cause of offspring) in about 2-4% of cases.

Spinal muscular atrophy affects individuals from all ethnic groups, unlike other well-known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in rates of occurrence among ethnic groups. The overall prevalence of high school, of all kinds and across all ethnic groups, is in the range of 1 per 10,000 individuals; the gene frequency is about 1: 100, therefore, about one in 50 people are carriers. There are no known health consequences as carriers. One can study career status only if one's child is influenced by high school or with a sequenced SMN1 gene.

The affected brother usually has a very similar form of SMA. However, the emergence of different types of SMAs among siblings does exist - though rarely, these cases may be due to additional deNovo removal of the SMN genes, excluding NAIP gen, or the difference in the number of copies SMN2 .

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Diagnosis

The most severe manifestations of the high school spectrum can be seen in mothers at the end of their pregnancy with reduced or absent fetal movements. The symptoms are critical (including respiratory disorders and lack of eating) which usually leads to death within a few weeks. Compared with the lightest phenotype of SMA (adult onset), where muscle weakness can appear after decades and develop into wheelchair use but life expectancy does not change.

A more general clinical manifestation of the SMA spectrum that encourages diagnostic genetic testing:

• Progressive bilateral muscle weakness (Normally upper arm & leg more than hands and feet) is preceded by an asymptomatic period (all but the most severe type 0)
• Flattens the chest wall while taking a breath and belly bulge while taking a breather.
• hypotonia associated with absent reflexes.

While the above symptoms leads to high school, the diagnosis can only be confirmed with absolute certainty through genetic testing for the removal of the ex-bielelic 7 gene SMN1 which is the cause in more than 95% of cases. Genetic testing is usually performed using blood samples, and MLPA is one of the more commonly used genetic testing techniques, as it also allows to assign the number of copies of the SMN2 genes.

Preimplantation test

Preimplantation genetic diagnosis may be used for screening of affected embryos during in-vitro fertilization.

Prenatal testing

Prenatal testing for SMA is possible through sampling of chorionic villus, analysis of cell-free fetal DNA and other methods.

Testing operator

Those at risk of becoming carriers of SMN1 removal, and thus at risk of having children affected by high school, may undergo operator analysis using blood or saliva samples. The American College of Obstetricians and Gynecologists recommends everyone who thinks to be pregnant is tested to see if they are carriers.

Regular screening

Regular prenatal or neonatal screening for controversial high school, due to cost, and due to disease severity. Some researchers have concluded that population screening for high schools is not cost-effective, at a cost of $ 5 million per case avoided in the United States in 2009. Others conclude that high school meets the criteria for relevant screening and testing programs should be offered to all couples. The main argument for neonatal screening is that in type I SMA, there is a critical period of time to begin therapy to reduce muscle loss and proactive maintenance in nutrition.

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Management

Clinical management of individuals with SMA varies by severity/type. Individual patient management with the same type of SMA may vary. In the most severe form (type 0/1), individuals have the greatest muscle weakness that requires rapid intervention. While the mildest form (type 4/adult onset), individuals may not seek certain aspects of care until later (several decades) in life. While the types of SMAs and individuals between each type may be different, therefore certain aspects of individual care can be different.

Respiratory care

Respiratory system is the most common system to be affected and complications are the leading cause of death in SMA type 0/1 and 2. SMA type 3 can have the same breathing problem, but it is less frequent. Complications arising from weakening of the intercostal muscle due to lack of stimulation of the nerves. The diaphragm is less affected than the intercostal muscle. Once weakened, the muscles never fully recover the same functional capacity to aid in breathing and coughing and other functions. Therefore, breathing is more difficult and at risk of not getting enough oxygen/shortness of breath and not enough exit airway secretion. These problems occur more often during sleep, when the muscles are more relaxed. Swallowing muscles in the pharynx can be affected, causing aspiration coupled with a poor cough mechanism increases the chance of infection/pneumonia. Mobilizing and clearing secretions involves manual or mechanical chest physiotherapy with postural drainage, and manual or mechanical coughing aids. To help breathe, non-invasive ventilation (BiPAP) is often used and tracheostomy can sometimes be performed in more severe cases; both ventilation methods prolong survival to a comparable level, although tracheostomy prevents speech development.

Nutrition

The more severe the type of SMA, the more likely it is to have health problems related to nutrition. Health problems can include difficulty in feeding, opening the jaw, chewing and swallowing. Individuals with such difficulty can increase the risk of excess or malnutrition, failure to develop and aspiration. Other nutritional problems, especially in non-outpatient individuals (types that are heavier than high school), include foods that do not pass through the stomach fast enough, gastric reflux, constipation, vomiting and bloating. In it, it may be necessary in type I SMA and people with type II who are more severe to have a filler or gastrostomy tube. In addition, metabolic abnormalities resulting from high school disturbances? fat-oxidation of muscle and can cause organic acidemia and consequently muscle damage, especially when fasting. It is recommended that people with high school, especially those with more severe forms of disease, reduce fat intake and avoid prolonged fasting (ie, eat more often than healthy people) and choose softer foods to avoid aspiration. During an acute illness, especially in children, nutritional problems may first be present or may aggravate existing problems (eg aspiration) and cause other health problems such as electrolytes and blood sugar disorders.

Orthopedics

Skeletal problems associated with weak muscles in the SMA include tight joints with limited range of motion, pelvic dislocation, spinal deformity, osteopenia, increased risk of fractures and pain. Weak muscles that usually stabilize the joints such as the vertebral column lead to development of kyphosis and/or scoliosis and joint contractures. Spinal fusion is sometimes performed on people with SMA I/II after they reach the age of 8-10 to reduce the pressure of the defective spine in the lungs. In addition, immobile individuals, posture and positioning on mobility devices as well as range of motion exercises, and bone strengthening can be important to prevent complications. People with high school may also benefit from various forms of physiotherapy, occupational therapy and physical therapy.

Mobility support

Orthotic devices can be used to support the body and to help walk. For example, orthotics such as AFO (ankle foot orthos) are used to stabilize the legs and to help the gait, TLSOs (torral sacral lumbar thorax) are used to stabilize the torso. Assistive technology can help in managing the movement and daily activities and greatly improve the quality of life.

Cardiology

Although the heart is not a matter of regular concern, the relationship between high school and certain heart conditions has been suggested.

Mental health

High school children are no different from the general population in their behavior; their cognitive development can be slightly faster, and certain aspects of their intelligence are above average. Despite their disability, the people affected by high school reported high levels of satisfaction from life.

Palliative care in high schools has been standardized in the Consensus Statement for Standard of Care in Spinal Muscular Atrophy that has been recommended for adoption of standards worldwide.

Medication

Nusinersen is the only drug approved to treat spinal muscular atrophy. It is administered directly to the central nervous system using intrathecal injection. It was approved by the European Commission in a centralized procedure in June 2017.

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Prognosis

Lack of pharmacological treatment, people with high schools tend to deteriorate over time. Recently, survival has increased in high school patients with supportive respiratory support and aggressive and proactive supportive nutrients.

The majority of children who were diagnosed with SMA type 0 and I did not reach the age of 4 years, respiratory problems repeatedly became the main cause of death. With proper care, a milder case of type I SMA (which covers about 10% of all SMA1 cases) lives to adulthood. Long-term survival in Type I high schools is insufficient; However, recent advances in respiratory support seem to have lowered mortality.

In SMA type II, the course of the disease is slower for progress and less life expectancy than a healthy population. Death before the age of 20 years is common, although many people with high school live to be parents and grandparents. SMA type III has a normal life expectancy or almost normal if the standard of care is followed. Type IV, onset of high school adult usually means only impaired mobility and does not affect life expectancy.

In all types of high school, physiotherapy has been shown to delay the progression of the disease.

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Direction of research

Because the underlying genetic cause of SMA was identified in 1995, several therapeutic approaches have been proposed and investigated which mainly focus on increasing the availability of SMN protein in motor neurons. The main research directions are as follows:

SMN1 gene switch

Gene therapy in high schools aims to restore the function of the SMN1 gene through the insertion of specially made nucleotide sequences (a SMN1 transgene) into the cell nucleus using viral vectors; scAAV-9 and scAAV-10 are the main viral vectors under investigation.

Only one program has reached the clinical stage:

• AVXS-101 - proprietary biology being developed by Avexis using self-complementary adeno-associated virus type 9 (scAAV-9) as a vector for delivering transgen SMN1 . In June 2016, phase I clinical trials were underway, with preliminary published results showing a clear increase in treated infants compared with the natural course of the disorder. In February 2017, two important trials of SMA1 infants have been announced to begin in 2017.

Working on developing gene therapy for high school was also conducted at the Institut de Myologie in Paris and at the University of Oxford.

SMN2 alternative splicing modulation

This approach aims to modify the alternate splicing of the SMN2 gene thereby forcing it to encode a higher percentage of the full-length SMN protein. Sometimes it's also called gene conversion, because it tries to transform the SMN2 gene functionally into the SMN1 gene.

The following splicing modulator has reached the stage of clinical development:

• Branaplam (LMI070, NVS-SM1) is an exclusive small molecule experimental drug administered orally and developed by Novartis. In October 2017 the compound remained in phase II clinical trials in infants with type 1 SMA while trials in other categories of patients were under development.
• RG7916 is a small proprietary molecule drug administered orally and developed by PTC Therapeutics in collaboration with Hoffmann-La Roche and the High School Foundation. In October 2016, the RG7916 has advanced to phase II trials in all types of ages and high schools.

From a discontinued clinical stage molecule, RG3039, also known as Quinazoline495, is an exclusive quinazoline derivative developed by Repligen and licensed to Pfizer in March 2014 that was stopped shortly after, after only completing phase I experiments. PTK-SMA1 is a molecular splicing modulator small group belonging to the tetracycline group developed by Paratek Pharmaceutical and will enter clinical development in 2010 that never took place. RG7800 is a molecule similar to RG7916, developed by Hoffmann-La Roche and tested in high school patients by 2015, whose development is endlessly restricted due to long-term animal toxicity.

The basic research has also identified other compounds that modify SMN2 in vitro splicing, such as sodium orthovanadate and aclarubicin. Morpholino-type oligonucleotides, with the same cellular target as nusinersen, remain the subject of intensive research, including at University College London and at Oxford University.

SMN2 gene activation

This approach aims to increase the expression (activity) of the SMN2 gene, thereby increasing the number of complete SMN proteins available. Oral salbutamol (albuterol), a popular asthma medication, exhibits therapeutic potential in high school both in vitro and in three small-scale clinical trials involving patients with SMA types 2 and 3, it offers breathing benefits.

Some compounds initially show promise but fail to demonstrate efficacy in clinical trials:

• Butyrates (sodium butyrate and phenylbutathic sodium) are promising in vitro studies but clinical trials in symptomatic people do not confirm their efficacy. Other clinical trials of pre-symptomatic infants of 1-2 infants were completed by 2015 but no results were published.
• Valproic acid was widely used in high school on an experimental basis in the 1990s and 2000s because in vitro research suggested its moderate effectiveness. However, it shows no efficacy in concentrations that can be achieved when undergoing major clinical trials. It has also been suggested that it may be effective in a subset of people with high school but its action can be suppressed by fatty acid translocase in others. Others think it may actually aggravate the symptoms of high school.
• Hydroxycarbamide (hydroxyurea) has been shown to be effective in mouse models and then commercially studied by Novo Nordisk, Denmark, but has no effect on people with high school in subsequent clinical trials.

Compounds that increase SMN2 in vitro activity but do not work to the clinical stage include growth hormone, various histone deacetylase inhibitors, benzamide M344, hydroxamic acid (CBHA, SBHA, entinostat, panobinostat , trichostatin A, vorinostat), prolactin and natural polyphenol compounds such as resveratrol and curcumin. Celecoxib, p38 line activator, is sometimes used off-label by people with high school based single animal studies but such use is not supported by clinical stage research.

SMN stabilization

SMN Stabilization aims to stabilize the SMN protein? 7, short-lived defect proteins encoded by the SMN2 gene, so as to support the nerve cells.

No compounds are brought to the clinical stage. Aminoglycosides demonstrate the ability to increase the availability of SMN protein in two studies. Indoprofen offers several promises in vitro .

Neuroprotection

Neuroprotective drugs aim to enable the survival of motor neurons even with low levels of SMN protein.

• Olesoxime is a proprietary neuroprotective compound developed by the French company Trophos, later acquired by Hoffmann-La Roche, which exhibits a stabilizing effect in phase II clinical trials involving people with SMA types 2 and 3. The development is discontinued at 2018 as competition with Spinraza and data worse than expected comes from open label extension experiments.

Of the clinically researched compounds that did not show efficacy, thyrotropin-releasing hormone (TRH) was promising in an uncontrolled open clinical trial but was not proven to be effective in a double blind placebo-controlled trial. Riluzole, a drug that has mild clinical benefit on amyotrophic lateral sclerosis, was proposed to be tested similarly in high school, but 2008-2010 trials in SMA types 2 and 3 were discontinued earlier due to a lack of satisfactory outcomes.

Compounds that have neuroprotective effects in in vitro studies but have not moved to in-vivo studies include? antibiotic-lactam (eg, ceftriaxone) and follistatin.

Muscle recovery

This approach aims to counter the influence of SMA by targeting muscle tissue instead of neurons.

• CK-2127107 (CK-107) is a skeletal troponin activator developed by Cytokinetics in collaboration with Astellas. This drug aims to increase muscle reactivity despite lowering nerve signals. In October 2016, this molecule is in phase II clinical trials in adolescents and adults with SMA types 2, 3, and 4.

Stem cells

Until 2016, there has been no significant breakthrough in stem cell therapy in high school. An experimental program to develop stem cell-based therapy products for high school runs, with financial support from high school communities, by US company California Stem Cell starting from 2005. It was discontinued in 2010, unable to enter the clinical stage, and the company no longer exists after that.

In 2013-2014, a small number of SMA1 children in Italy receive stem cell injections mandated after Stamina fraud, but treatment is reported to have no effect.

While stem cells never form part of a recognized therapy for high school, a number of private companies, usually located in countries with loose regulatory oversight, take advantage of media hype and market stem cell injection as a "cure" for a variety of disorders including SMA. The medical consensus is that the procedure does not offer clinical benefits while carrying significant risks, therefore people with high school are advised against them.

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Registries

People with high school in the EU can participate in clinical research by entering their details into registries administered by TREAT-NMD.

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See also

• Floppy baby syndrome
• Motor neuron disease
• Spinal muscular atrophy

src: www.musculardystrophyuk.org

References

src: cdn.stemcellthailand.org

Further reading

• Parano, E; Pavone, L; Falsaperla, R; Trifiletti, R; Wang, C (August 1996). "The molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy". Annals of Neurology . 40 (2): 247-51. doi: 10.1002/ana.410400219. PMIDÃ, 8773609.
• Wang C. H. (2007). "Consensus Statement for Standard of Care in Spinal Muscular Atrophy". Journal of Child Neurology . 22 : 1027-1049. doi: 10.1177/0883073807305788.

src: dmm.biologists.org

External links

• SMA at NINDS
• Spine muscle atrophy in Curlie (based on DMOZ)

Source of the article : Wikipedia